The role of SCFAs in iPS podocyte injury and their action in diabetic nephropathy

Chronic kidney disease CKD is an inflammatory condition that is increasing in prevalence around the world. Diabetes and obesity are the primary cause of kidney dysfunction1, suggesting that diet is an important environmental factor for kidney disease2. Proteinuria is one of the first signs of the kidney disease and occurs in up to ~40% of people with diabetes, and these usually progress to diabetic nephropathy characterized by loss or dysfunction of podocytes. The tissue damage triggered by inflammatory responses is driven mainly by macrophages and neutrophils leading to fibrotic events and resulting in loss of renal function. The extent to which diet, the gut microbiota and their primary metabolites the SCFAs account for the progression of renal disease is unknown. One model is that disrupted gut homeostasis by deficient production of SCFAs directly affects systemic and adipose inflammation, cholesterol and lipid levels in the blood, insulin sensitivity and ultimately podocyte function. Another mechanism by which SCFAs modulate cell function is through inhibition of histone deacetylases (HDAC)11. HDACs regulate chromatin remodeling and gene expression, as well as the role of numerous transcription factors in immune cells but also at the level of the podocytes12. For instance, epigenetic modifications modulate TGFβ signaling, inflammation, profibrotic genes, and the epithelial-to-mesenchymal transition, promoting renal fibrosis and progression of CKD13. Also, patients with kidney disease and chronic inflammation have lower ratios of HpaII/MspI, correlating with aberrant DNA methylation14. Epigenetic modifications also are essential for reprogramming somatic cells into induced pluripotent stem (iPS) cells15. Thus, podocyte epigenome can be targeted by SCFAs for in vitro intervention for the prevention or reduction of proteinuria. How will iPS podocytes benefit diabetes patients? Like other stem cells, iPS cells can proliferate indefinitely in vitro, creating a theoretically unlimited source of cells. Podocyte research has been hampered by the lack of suitable models that permit the direct study of factors regulating podocyte survival and function. Although the primary culture of human podocytes is possible, cells only replicate for a short term and cannot be maintained over long periods. In contrast, we have shown that podocytes derived from iPS cells that support characteristic podocyte features 16, can undergo long-term proliferation, and therefore may provide a test-bed for therapeutic discovery and the understanding of podocyte replacement for future kidney cell therapies. In vitro kidney-disease modeling offers a powerful tool for the investigation of podocyte defects underlying diabetes-related kidney failure and a platform for screening novel and existing therapeutic compounds. Like other stem cells, iPS cells can proliferate indefinitely in vitro, creating a theoretically unlimited source of cells. Additionally, iPS cells can be used as therapeutically relevant systems for modeling diseases and potentially as an approach for cellular replacement [reviewed in 17]. In light of recent findings involving the action of SCFA through receptor activation and epigenetic remodeling, we hypothesize that damage in kidney podocytes and tubular epithelial cells during the progression of nephropathy can be controlled or even decreased by modification of the gut microbiota and SCFA production. Therefore, the overall aim of this research is to understand the relevance of SCFAs and its mechanisms of protection in podocyte modeling. This concept proposal is to determine how diet, microbiota, and gut microbial metabolites (SCFAs) can modulate the progression of renal damage, and to reveal the molecular mechanisms (GPCR-mediated or inhibition of HDACs) in podocyte damage.